Affimer Tagged Cubosomes: Targeting of Carcinoembryonic Antigen Expressing Colorectal Cancer Cells Using In Vitro and In Vivo Models.
Affimer Tagged Cubosomes: Targeting of Carcinoembryonic Antigen Expressing Colorectal Cancer Cells Using In Vitro and In Vivo Models.
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DOI：
10.1021/acsami.1c21655
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发表时间：
2022-03-09
影响因子：
9.5
通讯作者：
Millner, Paul A.
中科院分区：
文献类型：
--
作者：
Pramanik, Arindam;Xu, Zexi;Shamsuddin, Shazana H.;Khaled, Yazan S.;Ingram, Nicola;Maisey, Thomas;Tomlinson, Darren;Coletta, P. Louise;Jayne, David;Hughes, Thomas A.;Tyler, Arwen I. I.;Millner, Paul A.
纳米药物虽然已被批准用于癌症治疗，但存在许多挑战，例如低稳定性，快速清除和非特异性导致脱靶毒性。立方体是多孔溶致液晶纳米颗粒，其作为药物递送载体已经显示出很大的前提;然而，它们在体内的行为在很大程度上未被探索，阻碍了临床转化。在这里，我们已经设计了基于空间群Im 3 m的立方体，其装载有乙酰丙酮铜作为模型药物，并且其表面首次通过无铜点击化学用Affimer蛋白进行功能化，以主动靶向LS 174 T结直肠癌细胞上过表达的癌胚抗原。与非靶向立方体不同，Affimer标记的立方体不仅在体外（2D单层细胞培养和3D球状体模型）而且在体内结肠直肠癌小鼠异种移植物中显示出与正常细胞相比在癌细胞中的优先蓄积，同时在其他重要器官中显示出低非特异性吸收和毒性。在靶向递送时，与非癌细胞相比，癌性球状体具有最大的细胞死亡。与非靶向组相比，接受靶向载药立方体的异种移植物在肿瘤组织中的药物积累比肝脏、肾脏和其他重要器官高5-7倍，肿瘤生长显着减少，存活率提高。这项工作包括Affimer靶向cubosomes作为癌症治疗剂的第一次彻底的临床前研究。
Nanomedicines, while having been approved for cancer therapy, present many challenges such as low stability, rapid clearance, and nonspecificity leading to off-target toxicity. Cubosomes are porous lyotropic liquid crystalline nanoparticles that have shown great premise as drug delivery vehicles; however, their behavior in vivo is largely underexplored, hindering clinical translation. Here, we have engineered cubosomes based on the space group Im3m that are loaded with copper acetylacetonate as a model drug, and their surfaces are functionalized for the first time with Affimer proteins via copper-free click chemistry to actively target overexpressed carcinoembryonic antigens on LS174T colorectal cancer cells. Unlike nontargeted cubosomes, Affimer tagged cubosomes showed preferential accumulation in cancer cells compared to normal cells not only in vitro (2D monolayer cell culture and 3D spheroid models) but also in vivo in colorectal cancer mouse xenografts, while exhibiting low nonspecific absorption and toxicity in other vital organs. Cancerous spheroids had maximum cell death compared to noncancerous cells upon targeted delivery. Xenografts subjected to targeted drug-loaded cubosomes showed a 5–7-fold higher drug accumulation in the tumor tissue compared to the liver, kidneys, and other vital organs, a significant decrease in tumor growth, and an increased survival rate compared to the nontargeted group. This work encompasses the first thorough preclinical investigation of Affimer targeted cubosomes as a cancer therapeutic.
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DOI：
10.1002/anie.201804067
发表时间：
2019-03-04
期刊：
Angewandte Chemie (International ed. in English)
影响因子：
--
作者：
Barriga HMG;Holme MN;Stevens MM
通讯作者：
Stevens MM
影响因子：
16.6
作者：
He H;Rahimi K;Zhong M;Mourran A;Luebke DR;Nulwala HB;Möller M;Matyjaszewski K
通讯作者：
Matyjaszewski K
影响因子：
3.9
作者：
Aleandri, Simone;Bandera, Davide;Landau, Ehud M.
通讯作者：
Landau, Ehud M.
影响因子：
14
作者：
Jain, Vikas;Swarnakar, Nitin K.;Jain, Narendra K.
通讯作者：
Jain, Narendra K.
影响因子：
3.9
作者：
Caltagirone, Claudia;Falchi, Angela Maria;Murgia, Sergio
通讯作者：
Murgia, Sergio